Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells

Goffinet, Marine; Thoulouzan, M.; Pradines, Anne; Lajoie‐Mazenc, Isabelle; Weinbaum, Carolyn; Faye, Jean-Charles; Séronie-Vivien, Sophie

doi:10.1186/1471-2407-6-60

Cited by 78 publications

(72 citation statements)

References 29 publications

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“…However, with respect to the in vitro effects of ZOL on prostate cancer cells, inhibition of geranylgeranylation seems to be more critical than the inhibition of farnesylation (34,35,44). Here, we have presented evidence that the synergistic action of SAHA and ZOL was also conferred through inhibiting geranylgeranylation rather than farnesylation.…”

Section: Discussionmentioning

confidence: 80%

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Sonnemann¹,

Bumbul²,

Beck

2007

Molecular Cancer Therapeutics

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Bisphosphonates are widely used agents for the treatment of malignant bone disease. They inhibit osteoclastmediated bone resorption and can have direct effects on cancer cells. In this study, we investigated whether the anticancer activity of the third-generation bisphosphonate zoledronic acid (ZOL) could be enhanced by combination with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). We found that ZOL and SAHA cooperated to induce cell death in the prostate cancer cell lines LNCaP and PC-3. The effect was synergistic, as evidenced by combination index isobologram analysis. ZOL and SAHA synergized to induce dissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNA fragmentation, showing that the combination of ZOL and SAHA resulted in the initiation of apoptosis. Because ZOL acts by inhibiting the mevalonate pathway, thereby preventing protein prenylation, we explored whether the mevalonate pathway was also the target of the cooperative action of ZOL and SAHA. We found that geranylgeraniol, but not farnesol, significantly reduced ZOL/SAHA-induced cell death, indicating that the synergistic action of the agents was due to the inhibition of geranylgeranylation. Consistently, a direct inhibitor of geranylgeranylation, GGTI-298, synergized with SAHA to induce cell death, whereas an inhibitor of farnesylation, FTI-277, had no effect. In addition, SAHA synergized with mevastatin, an inhibitor of the proximal enzyme in the mevalonate pathway. These in vitro findings provide a rationale for an in vivo exploration into the potential of combining SAHA and ZOL, or other inhibitors of the mevalonate pathway, as an effective strategy for anticancer therapy.

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Section: Discussionmentioning

confidence: 80%

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Sonnemann¹,

Bumbul²,

Beck

2007

Molecular Cancer Therapeutics

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“…IPP is further metabolized endogenously into an ATP analogue ApppI, which is able to induce apoptosis in cells by inhibiting mitochondrial adenine nucleotide translocase (ANT), causing also a loss of the mitochondrial membrane potential [17,20]. Several studies have demonstrated that the interruption of the protein prenylation is a major contributor to the anticancer action of N-BPs [7,36,37], whereas the role and the significance of the additional mechanism of action, accumulation of IPP/ApppI, is less clear.…”

Section: Discussionmentioning

confidence: 99%

“…HMGR is controlled by negative feedback overcome statin and N-BP-induced apoptosis in many cell types [7,8,15,16,27,28]. In addition, we have evidence that GGOH may possess the capacity to inhibit ZOLinduced IPP/ApppI formation in tumor cells [20], but the mechanism underlying this effect is not known.…”

Section: Introductionmentioning

confidence: 91%

“…These effective inhibitors of bone resorption are successfully and widely used pharmaceutical agents for treatment of diseases characterized by excessive bone loss [3][4][5]. Furthermore, extensive evidence from preclinical research have demonstrated that N-BPs exhibit antitumor activity in a variety of cancer models [6][7][8][9][10]. Importantly, there is now clinical evidence that the addition of ZOL to endocrine therapy can improve disease-free survival in premenopausal women with estrogen-responsive early breast cancer, indicating that bisphosphonates exert clinical antitumor effects [11].…”

Section: Introductionmentioning

confidence: 99%

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Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Räikkönen

Mönkkönen

Auriola

et al. 2010

Biochemical Pharmacology

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To cite this version:Johanna Räikkönen, Hannu Mönkkönen, Seppo Auriola, Jukka Mönkkönen. Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochemical Pharmacology, Elsevier, 2009, 79 (5) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 35A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via

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“…Bisphosphonates (Fig. 2B), which have been used to treat osteoporosis and similar diseases in millions of people (25), have been shown to be efficient FPPS (26) and, in some cases, GGPPS (27) inhibitors, and one approach for the development of drugs for neglected diseases is the repositioning of drugs currently in use (28). Bisphosphonates have also been found to be active against a variety of protozoan parasites, for example, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani (26,(29)(30)(31), Cryptosporidium parvum (32), Entamoeba histolytica (33), Toxoplasma gondii (34), and Plasmodium species (26,33,(35)(36)(37).…”

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confidence: 99%

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

Ziniel

Desai

Cass

et al. 2013

Antimicrob Agents Chemother

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dSchistosomiasis affects over 200 million people worldwide, with over 200,000 deaths annually. Currently, praziquantel is the only drug available against schistosomiasis. We report here that Schistosoma mansoni farnesyl diphosphate synthase (SmFPPS) and geranylgeranyl diphosphate synthase (SmGGPPS) are potential drug targets for the treatment of schistosomiasis. We expressed active, recombinant SmFPPS and SmGGPPS for subsequent kinetic characterization and testing against a variety of bisphosphonate inhibitors. Recombinant SmFPPS was found to be a soluble 44.2-kDa protein, while SmGGPPS was a soluble 38.3-kDa protein. Characterization of the substrate utilization of the two enzymes indicates that they have overlapping substrate specificities. Against SmFPPS, several bisphosphonates had 50% inhibitory concentrations (IC 50 s) in the low micromolar to nanomolar range; these inhibitors had significantly less activity against SmGGPPS. Several lipophilic bisphosphonates were active against ex vivo adult worms, with worm death occurring over 4 to 6 days. These results indicate that FPPS and GGPPS could be of interest in the context of the emerging resistance to praziquantel in schistosomiasis therapy.

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Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells

Abstract: Background: Nitrogen-containing bisphosphonates (N-BPs) have been designed to inhibit osteoclast-mediated bone resorption. However, it is now accepted that part of their anti-tumor activities is related to interference with the mevalonate pathway.

Cited by 78 publications

References 29 publications

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Synergistic activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid and the bisphosphonate zoledronic acid against prostate cancer cells in vitro

Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

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